Influence of Donor C3 Allotype on Late Renal-Transplantation Outcome

Brown, Katelyn; Kondeatis, E; Vaughan, R. W.; Kon, Sui Phin; Farmer, Chris; Taylor, John; He, Xiang; Johnston, Atholl; Horsfield, Catherine; Janssen, B.J.C.; Gros, Piet; Zhou, Wuding; Sacks, Steven H.; Sheerin, Neil

doi:10.1056/nejmoa052825

Cited by 174 publications

(114 citation statements)

References 32 publications

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“…The same variant appears to affect the outcome of renal transplantation. 74 A 1972 study of the fast and slow variants found no difference in haemolytic activity. 75 There have been no recent published functional studies of the effect of this polymorphism and so the mechanism of its effect in AMD is not yet known.…”

Section: Genetic Variants Of Complement Genes Associated With Amd Andmentioning

confidence: 96%

Complement in age-related macular degeneration: a focus on function

Bradley

Zipfel

Hughes

2011

Eye

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Age-related macular degeneration (AMD) is an inflammatory disease, which causes visual impairment and blindness in older people. The proteins of the complement system are central to the development of this disease. Local and systemic inflammation in AMD are mediated by the deregulated action of the alternative pathway of the complement system. Variants in complement system genes alter an individual's risk of developing AMD. Recent studies have shown how some risk-associated genetic variants alter the function of the complement system. In this review, we describe the evolution of the complement system and bring together recent research to form a picture of how changes in complement system genes and proteins affect the function of the complement cascade, and how this affects the development of AMD. We discuss the application of this knowledge to prevention and possible future treatments of AMD.

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Section: Genetic Variants Of Complement Genes Associated With Amd Andmentioning

confidence: 96%

Complement in age-related macular degeneration: a focus on function

Bradley

Zipfel

Hughes

2011

Eye

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“…Complement is important at many stages during the course of a kidney transplant: complement polymorphisms may alter outcome after transplantation [63] , complement gene expression is increased in preimplantation biopsies and this can predict outcome [64] , complement has a role in the development of ischaemia reperfusion injury [65] and augments the alloimmune response [66] . All of these factors may impact upon longterm transplant outcome, however it is the role of complement in antibody mediated rejection (AMR) that has generated most interest recently.…”

Section: Complement and Progressive Loss Of Transplant Functionmentioning

confidence: 99%

Complement activation in progressive renal disease

Fearn

Sheerin

2015

WJN

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ritis, thrombotic microangiopathies and transplant reje ction. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease. Core tip: Complement activation occurs in progressive chronic kidney disease and may contribute to the chronic inflammation that is characteristically found in the kidney. It is therefore possible that inhibiting complement activation would reduce inflammation, lead to reduced fibrosis and preservation of renal function. INTRODUCTIONChronic kidney disease (CKD) is recognised worldwide as a major public health problem [1] . In 2007 the United Kingdom age-standardised prevalence of CKD stages 3-5 was 8.5% (10.6% in females and 5.8% in males) [2] and similar prevalences have been described in other countries. In 2012 in the United Kingdom, the number of new patients requiring renal replacement therapy was 6891, equating to 108 patients per million population, with diabetes and glomerulonephritis being the two most common diagnoses in incident dialysis patients. Although not all patients with CKD will progress to renal failure, all stages of CKD are associated with increased AbstractChronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic nonresolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in preclinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomeruloneph morbidity and mortality [1] . Tubulointerstitial inflammation and fibrosis is a major factor in the progressive loss of renal function in most kidney diseases [3] . The process is complex due to the number of interacting pathways which ultimately result in the replacement of functioning nephrons with scar tissue. Cellular stress and injury induces an inflammatory and pro-fibrogenic response involving growth factors [4][5][6] and pro-inflammatory cytokines as well as activation of the renin-angiotensin system. This leads to a chronic inflammatory cell infiltrate, increasing numbers of activated fibroblasts (myofibroblasts) and excessive matrix deposition. There is evidence from preclinical models that the immune system is important in the development of renal fibrosis [7,8] . A component of the innate immune system that may be important in driving renal inflammation is the complement system, which can directly affect cell function and also influence the adaptive immune response. REVIEW COMPLEMENT SYSTEMTh...

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“…Carries of C3F allele are at risk for the development of age-related macular degeneration (AMD) [46], partial lipodystrophy (PD) [51], and various types of GN: membranoproliferative glomerulonephritis type II (MPGN II, presently known as dense deposit disease, DDD) [51,52], IgA nephropathy (IgAN) [53,54] and systemic vasculitis (SV) [55,56]. Surprisingly, C3F allele has been shown to have a protective effect on transplant kidney, and its presence in donor's kidney may prolong the graft survival [57]. The common C3S/F comprises approximately 98% of all C3 phenotypes.…”

Section: The Genetic Background Of the Ap Abnormalities In Glomerularmentioning

confidence: 99%

The role of the alternative pathway of complement activation in glomerular diseases

2018

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The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called 'thick-over.' A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.

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Influence of Donor C3 Allotype on Late Renal-Transplantation Outcome

Cited by 174 publications

References 32 publications

Complement in age-related macular degeneration: a focus on function

Complement in age-related macular degeneration: a focus on function

Complement activation in progressive renal disease

The role of the alternative pathway of complement activation in glomerular diseases

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